1. Field of the Invention
The present invention relates to novel aminoglycoside antibiotics characterized in that they are effective against bacteria which induce clinically severe infectious diseases, particularly against methicillin-resistant Staphylococcus aureus (MRSA), and have a low level of nephrotoxicity. The present invention also relates to novel intermediates useful for the production of the aminoglycoside antibiotics.
2. Background Art
In recent years, drug resistant bacteria resistant to antimicrobial agents used for the treatment of infectious diseases have appeared, and the treatment of infectious diseases induced by the resistant bacteria has become a major problem in clinical practice. In particular, MRSA is known as one of major drug resistant bacteria, which rapidly propagate through hospital infection and induce clinically severe infectious diseases, and the development of therapeutic agents for the infectious diseases has been energetically made.
Aminoglycoside antibiotics have a broad antimicrobial spectrum from gram-positive bacteria to gram-negative bacteria and have potent sterilizing power. Accordingly, the aminoglycoside antibiotics are expected to function as promising medicaments which can overcome various resistant bacteria including MRSA, and studies on the derivatives have been continuously carried out.
For example, Journal of Antibiotics, Vol. 24, 1971, p. 485 discloses that various derivatives of kanamycin, which is an aminoglycoside antibiotic, could be synthesized and 3′,4′-deoxykanamycin B (dibekacin) could be discovered from the kanamycin derivatives. Dibekacin is widely used as a chemotherapeutic agent effective for resistant bacteria since 1975.
Journal of Antibiotics, Vol. 26, 1973, p. 412 discloses (S)-1-N-(4-amino-2-hydroxybutyryl)dibekacin (arbekacin) obtained by acylating the amino group at 1-position of dibekacin with an aminohydroxybutyric acid. Further, Japanese Patent Publication No. 10719/1988 discloses a production process of arbekacin.
Arbekacin has been used as a therapeutic agent for MRSA infectious diseases from the end of 1990. Arbekacin is known to have a broad antimicrobial spectrum from gram-positive bacteria including MRSA to gram-negative bacteria including Pseudomonas aeruginosa. Ten years or more have passed since arbekacin has become used as a therapeutic agent for MRSA infectious diseases. Despite this fact, there is no report about a severely enhanced resistance. On the other hand, JAPANESE SOClETY OF CHEMOTHERAPY, Vol. 50, 2002, p. 494 reports that some clinically isolated MRSAs have lowered sensitivity to arbekacin.
Studies on various arbekacin analogues have been continuously carried out. For example, WO 2005/070945 discloses that a group of compounds, characterized in that the steric configuration of the site corresponding to the 5-position of arbekacin has been inverted and various substituents have been introduced, have antimicrobial activity against MRSA.
On the other hand, nephrotoxicity is known, from long ago, as a side effect of aminoglycoside antibiotics. There is also a report about clinical influence of arbekacin (Japanese Patent Laid-Open No. 164696/1980) on the kidney (JAPANESE SOClETY OF CHEMOTHERAPY, Vol. 51, 2003, p. 717).
In subject No. F-716 in the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (2004), the present inventors describe, regarding an arbekacin analogue (compound No. TS2037: 5,4″-diepiarbekacin) described in WO 2005/070945, the results of the evaluation of nephrotoxicity using proximal uriniferous tubule epithelial cells of the kidney of pigs and using β-N-acetyl-D-glucosaminidase (hereinafter referred to as “NAG”) as an index. The results show that the nephrotoxicity of the arbekacin analogue is higher than that of arbekacin.
Studies on various methods for reducing the nephrotoxicity of aminoglycoside antibiotics have hitherto been made. The combined use of an aminoglycoside antibiotic and a compound for reducing the nephrotoxicity is reported as one of such methods. For example, fosfomycin is known to reduce the nephrotoxicity of some aminoglycoside antibiotics. Further, in a test using rats, there is a report that the combined use of fosfomycin and arbekacin reduces the nephrotoxicity (The Japanese Journal of Antibiotics, Vol. 47, 1994, p. 664).
A method using the so-called TDM (therapeutic drug monitoring), in which a high level of therapeutic effect is realized while suppressing the side effect by making a medicine administration plan based on Pharmacokinetics and Pharmacodynamics, has recently been studied. For example, there is a report that TDM is also utilized for anti-MRSA treatment with arbekacin (JAPANESE SOClETY OF CHEMOTHERAPY, Vol. 51, 2003, p. 717).
When conventional aminoglycoside antibiotics, which are used clinically, are used solely, however, it is still required to reduce the nephrotoxicity while maintaining a broad antimicrobial spectrum and potent antimicrobial activity against bacteria, which induce severe infectious diseases, including MRSA. Accordingly, in aminoglycoside antibiotics, the development of a novel compound having a broad antimicrobial spectrum and potent sterilizing power and, at the same time, having a low level of nephrotoxicity has been desired. Further, for the conventional aminoglycoside antibiotics, the appearance of drug resistant bacteria has become a problem, and compounds, which have excellent antimicrobial activity also against the drug resistant bacteria, have been still required. Furthermore, when the production of excellent antibiotics is taken into consideration, studies on stable production of the antibiotics are also a critical issue.